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Molecular Diagnostics

Dynamic expression of Schlafen 11 (SLFN11) in circulating tumour cells as a liquid biomarker in small cell lung cancer

Abstract

Introduction

Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling.

Methods

SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response.

Results

Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine tumours expressed SLFN11 expression. In 64 blood samples from 42 SCLC patients, 83% (53/64) of samples had detectable CTCs, and SLFN11-positive CTCs were detected in 55% (29/53). Patients actively receiving platinum treatment had the lowest number of CTCs and a lower percentage of SLFN11-positive CTCs (p = 0.014). Analysis from patients with longitudinal samples suggest a decrease in CTC number and in SLFN11 expression that correlates with clinical response.

Conclusions

SLFN11 levels can be monitored in CTCs from SCLC patients using non-invasive liquid biopsies. The ability to detect SLFN11 in CTCs from SCLC patients adds a valuable tool for the detection and longitudinal monitoring of this promising biomarker.

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Fig. 1: SLFN11 levels in SCLC patient samples.
Fig. 2: SLFN11 levels in patient CTCs and tumours, and CTC-derived xenograft (CDX) models.
Fig. 3: Longitudinal assessment of CTCs and SLFN11 positivity in CTCs with corresponding radiographic images.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to acknowledge the patients who participated in this study and volunteered for blood draws (under protocol LAB10-0442) to help further our understanding of SCLC. We would also like to thank Patrice Hartsfield and Heather Napoleon from the protocol blood collection team. This work was supported by: The NIH/NCI CCSG P30-CA016672 (Bioinformatics Shared Resource); NIH/NCI R01-CA207295; NIH/NCI U01-CA213273; NIH/NCI R50-CA243698; The University of Texas-Southwestern and MD Anderson Lung SPORE (5 P50 CA070907); NIH T32 training grant (T32-CA009666); and CPRIT Early Clinical Investigator Award. and through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program and to the Byers Lab; The Andrew Sabin Family Fellowship; The Abell Hangar Foundation; the LUNGevity Foundation Career Development Award, and the Rexanna Foundation for Fighting Lung Cancer.

Funding

This work was supported by NIH T32 CA009666 (BZ); NIH/NCI R50-CA243698 (CS); University of Texas-Southwestern and MD Anderson Lung SPORE (5 P50 CA070907), The University of Texas MD Anderson Lung Cancer Moon Shot Program, The Andrew Sabin Family Fellowship, The Abell Hangar Foundation; the LUNGevity Foundation Career Development Award, the Rexanna Foundation for Fighting Lung Cancer, and CPRIT Early Clinical Investigator Award (CG); NIH/NCI U01-CA213273 and NIH R01-CA207295 (LB).

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Authors and Affiliations

Authors

Contributions

BZ, CAS, RJC, LAB and CMG: conceptualised this study. BZ, CAS, QW, PR, JF, LS, RW, LF, AJ, CG, JDS, JB and JJ contributed to methodology development, data curation and analyses of the study. VN, PA, LH, HT, AA, MN, JZ, WW and IW provided administration and resources support. JW, RW, LAB and CMG supervised and provided funding for the study. All authors contributed to the writing, editing and review of the manuscript.

Corresponding authors

Correspondence to Lauren A. Byers or Carl M. Gay.

Ethics declarations

Competing interests

IW received honorarium from Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Flame, Novartis, Sanofi, Daiichi Sankyo, Amgen, Oncocyte, and MSD; and received research support from Genentech, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. JZ served on advisory board for AstraZeneca, Novartis, Johnson and Johnson, Geneplus and received speaker’s fees from BMS, OrigMed, Innovent, grants from Merck, Novartis, Johnson and Johnson from outside the submitted work JS received stock options from Epic Sciences at the time of this work. MN reports research funding to institution: Mirati, Novartis, Checkmate, Ziopharm, AstraZeneca, Pfizer, Genentech; consulted for Mirati, Merk and served on advisory board for MSD; meal expenses from Ziopharm. LB received research funding from AstraZeneca, GenMab, Sierra Oncology, ToleroPharmaceuticals; served as an advisor/consultant for AstraZeneca, GenMab, Sierra Oncology, PharmaMar, AbbVie, Bristol-Myers Squibb, Alethia, Merck, Pfizer, Jazz Pharmaceuticals, Genentech, Debiopharm Group. CG received research funding from AstraZeneca; served as an adviser for Bristol-Myers Squibb, Jazz Pharmaceuticals, AstraZeneca, Kisoji; and served on the Speaker’s Bureau for AstraZeneca, Beigene.

Ethics approval and consent to participate

Participants underwent informed written consent to Institutional Review Board (IRB)-approved protocol LAB10-0442 (“Evaluation of blood-based test for the detection of circulating tumour cells and circulating proteins and microRNAs and molecular analysis for polymorphisms and mutations”). The study was performed in accordance with the Declaration of Helsinki.

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Zhang, B., Stewart, C.A., Wang, Q. et al. Dynamic expression of Schlafen 11 (SLFN11) in circulating tumour cells as a liquid biomarker in small cell lung cancer. Br J Cancer 127, 569–576 (2022). https://doi.org/10.1038/s41416-022-01811-9

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